This proposal requests support for a comprehensive training plan that will enable Heather Boger, PhD, to broaden, enhance, and refine her technical skills that are necessary for a productive independent research career. Dr. Boger will receive multifaceted training during the mentored phase (Year 1-2) of the award from a team of collaborating mentors that include training in molecular biology, electrochemistry, production of nanoparticles (microspheres), and statistics. The research plan that is proposed during the independent phase (Year 3-5) builds on this training and focuses more specifically on mechanisms involved with neurodegeneration. Aging and Parkinson's disease (PD), a known neurodegenerative disease resulting in motor impairments, has been associated with a reduction of glial cell line-derived neurotrophic factor (GDNF) in the substantia nigra, increased oxidative stress, and an increase in the indirect pathway of the basal ganglia circuitry (including increase dopamine D2 receptor expression, increased nigral glutamate release from overactive subthalamic nucleus neurons, and decreased nigrostriatal dopamine expression and function). We have demonstrated that a mouse model with a genetic reduction of GDNF have early-onset motor dysfunction and evidence of increased indirect pathway function, such as increased striatal D2 receptor expression and accelerated decline in nigrostriatal expression. However, it is not known whether a partial gene deletion of GDNF impacts subthalamic nucleus glutamate release into the substantia nigra and oxidative stress with age. Therefore, the overall hypothesis of this research proposal is that the intrinsic GDNF loss enhances nigrostriatal DAergic system dysfunction by increasing STN-nigral glutamate excitotoxicity via oxidative stress. To address this hypothesis, three specific aims have been formulated: Aim 1) The neuronal response to acute administration of GDNF is altered in mice with a genetic reduction of GDNF, Aim 2) Chronic administration of GDNF will alleviate the age-related effects of a partial loss of GDNF on DA function, and Aim 3) The progress DAergic loss due to less availability of GDNF dysregulates the glutamatergic input from the subthalamic nucleus in the substantia nigra, resulting in elevated oxidative stress and continued DAergic dysfunction. Findings from these studies will provide insight into the mechanisms underlying early-onset dopaminergic loss associated with a partial loss of GDNF and may identify therapeutic targets to reduce oxidative stress, nigrostriatal dopamine loss, and motor dysfunction occurring with aging and parkinsonism. In addition, results from these studies will serve to guide Dr. Boger's future independent research in the area of systems neuroscience. PUBLIC HEALTH RELEVANCE: Glial cell line-derived neurotrophic factor (GDNF) is reduced in Parkinson's disease patients and we have shown that mice with a partial loss of GDNF have accelerated age-related loss of motor function and nigrostriatal dopamine, but the relationship between GDNF reductions and dopamine loss is unknown. We propose that the dopamine loss as a result of long-term reduction of GDNF results in increased glutamate release from the subthalamic nucleus into the substantia nigra resulting in oxidative stress and continued dopaminergic damage. Furthermore, exogenous GDNF administration will alleviate the dopaminergic damage associated with increased glutamate toxicity as a result of a life-long reduction of GDNF.